scholarly journals Mapping of Epitopes Exposed on Intact Human Immunodeficiency Virus Type 1 (HIV-1) Virions: a New Strategy for Studying the Immunologic Relatedness of HIV-1

1998 ◽  
Vol 72 (11) ◽  
pp. 9384-9391 ◽  
Author(s):  
Phillipe N. Nyambi ◽  
Miroslaw K. Gorny ◽  
Lisa Bastiani ◽  
Guido van der Groen ◽  
Constance Williams ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Enzyme Linked Immunosorbent Assay ◽  
Virus Binding ◽  
Immunodeficiency Virus ◽  
New Strategy ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT To study the antigenic conservation of epitopes of human immunodeficiency virus type 1 (HIV-1) isolates of different clades, the abilities of human anti-HIV-1 gp120 and gp41 monoclonal antibodies (MAbs) to bind to intact HIV-1 virions were determined by a newly developed virus-binding assay. Eighteen human anti-HIV MAbs, which were directed at the V2, V3 loop, CD4-binding domain (CD4bd), C5, or gp41 regions, were used. Nine HIV-1 isolates from clades A, B, D, F, G, and H were used. Microtiter wells were coated with the MAbs, after which virus was added. Bound virus was detected after lysis by testing for p24 antigen with a noncommercial p24 enzyme-linked immunosorbent assay. The anti-V3 MAbs strongly bound the four clade B viruses and viruses from the non-B clades, although binding was weaker and more sporadic with the latter. The degrees of binding by the anti-V3 MAbs to CXCR4- and CCR5-tropic viruses were similar, suggesting that the V3 loops of these two categories of viruses are similarly exposed. The anti-C5 MAbs bound isolates of clades A, B, and D. Only weak and sporadic binding of all the viruses tested with anti-CD4bd, anti-V2, and anti-gp41 MAbs was detected. These results suggest that V3 and C5 structures are shared and well exposed on intact virions of different clades compared to the CD4bd, V2, and gp41 regions.

An Approach towards the Synthesis of Potential Metal-Chelating TSAO-T Derivatives as Bidentate Inhibitors of Human Immunodeficiency virus Type 1 Reverse Transcriptase

1998 ◽  
Vol 9 (5) ◽  
pp. 412-421 ◽  
Author(s):  
C Chamorro ◽  
M-J Camarasa ◽  
M-J Pérez-Pérez ◽  
E de Clercq ◽  
J Balzarini ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Parent Compound ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

Novel derivatives of the potent human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor TSAO-T have been designed, synthesized and tested for their in vitro antiretro-viral activity against HIV. These TSAO-T derivatives have been designed as potential bidentate inhibitors of HIV-1 RT, which combine in their structure the functionality of a non-nucleoside RT inhibitor (TSAO-T) and a bivalent ion-chelating moiety (a β-diketone moiety) linked through an appropriate spacer to the N-3 of thymine of TSAO-T . Some of the new compounds have an anti-HIV-1 activity comparable to that of the parent compound TSAO-T, but display a markedly increased antiviral selectivity. There was a clear relationship between antiviral activity and the length of the spacer group that links the TSAO molecule with the chelating moiety. A shorter spacer invariably resulted in increased antiviral potency. None of the TSAO-T derivatives were endowed with anti-HIV-2 activity.

scholarly journals Structure-Function Analysis of the Epitope for 4E10, a Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody

2006 ◽  
Vol 80 (4) ◽  
pp. 1680-1687 ◽  
Author(s):  
Florence M. Brunel ◽  
Michael B. Zwick ◽  
Rosa M. F. Cardoso ◽  
Josh D. Nelson ◽  
Ian A. Wilson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Function Analysis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Peptide Epitope ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
4E10 Antibody

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) neutralizing antibody 4E10 binds to a linear, highly conserved epitope within the membrane-proximal external region of the HIV-1 envelope glycoprotein gp41. We have delineated the peptide epitope of the broadly neutralizing 4E10 antibody to gp41 residues 671 to 683, using peptides with different lengths encompassing the previously suggested core epitope (NWFDIT). Peptide binding to the 4E10 antibody was assessed by competition enzyme-linked immunosorbent assay, and the Kd values of selected peptides were determined using surface plasmon resonance. An Ala scan of the epitope indicated that several residues, W672, F673, and T676, are essential (>1,000-fold decrease in binding upon replacement with alanine) for 4E10 recognition. In addition, five other residues, N671, D674, I675, W680, and L679, make significant contributions to 4E10 binding. In general, the Ala scan results agree well with the recently reported crystal structure of 4E10 in complex with a 13-mer peptide and with our circular dichroism analyses. Neutralization competition assays confirmed that the peptide NWFDITNWLWYIKKKK-NH2 could effectively inhibit 4E10 neutralization. Finally, to limit the conformational flexibility of the peptides, helix-promoting 2-aminoisobutyric acid residues and helix-inducing tethers were incorporated. Several peptides have significantly improved affinity (>1,000-fold) over the starting peptide and, when used as immunogens, may be more likely to elicit 4E10-like neutralizing antibodies. Hence, this study represents the first stage toward iterative development of a vaccine based on the 4E10 epitope.

Synthesis and in vitro anti-HIV-1 activity of a series of N-arylsulfonyl-3-propionylindoles

2016 ◽  
Vol 71 (5-6) ◽  
pp. 105-109 ◽  
Author(s):  
Zhiping Che ◽  
Yuee Tian ◽  
Zhenjie Hu ◽  
Yingwu Chen ◽  
Shengming Liu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Therapeutic Index ◽  
Effective Concentration ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

Abstract Fifteen N-arylsulfonyl-3-propionylindoles (3a–o) were prepared and preliminarily evaluated as in vitro inhibitors of human immunodeficiency virus type-1 (HIV-1). Three compounds 3c, 3g and 3i exhibited potent anti-HIV-1 activity with effective concentration (EC50) values of 0.8, 4.0 and 1.2 μg/mL, and therapeutic index (TI) values of 11.7, 16.6 and 84.1, respectively. N-(m-Nitro)phenylsulfonyl-3-propionyl-6-methylindole (3i) exhibited the most promising and best activity against HIV-1 replication. The cytotoxicity of these compounds was assessed as well.

scholarly journals Identification of a Critical Motif for the Human Immunodeficiency Virus Type 1 (HIV-1) gp41 Core Structure: Implications for Designing Novel Anti-HIV Fusion Inhibitors

2008 ◽  
Vol 82 (13) ◽  
pp. 6349-6358 ◽  
Author(s):  
Yuxian He ◽  
Jianwei Cheng ◽  
Jingjing Li ◽  
Zhi Qi ◽  
Hong Lu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Core Structure ◽  
Heptad Repeat ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) entry into the host cell involves a cascade of events and currently represents one of most attractive targets in the search for new antiviral drugs. The fusion-active gp41 core structure is a stable six-helix bundle (6-HB) folded by its trimeric N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR). Peptides derived from the CHR region of HIV-1 gp41 are potent fusion inhibitors that target the NHR to block viral and cellular membrane fusion in a dominant negative fashion. However, all CHR peptides reported to date are derived primarily from residues 628 to 673 of gp41; little attention has been paid to the upstream sequence of the pocket binding domain (PBD) in the CHR. Here, we have identified a motif (621QIWNNMT627) located at the upstream region of the gp41 CHR, immediately adjacent to the PBD (628WMEWEREI635). Biophysical characterization demonstrated that this motif is critical for the stabilization of the gp41 6-HB core. The peptide CP621-652, containing the 621QIWNNMT627 motif, was able to interact with T21, a counterpart peptide derived from the NHR, to form a typical 6-HB structure with a high thermostability (thermal unfolding transition [T m ] value of 82°C). In contrast, the 6-HB formed by the peptides N36 and C34, which has been considered to be a core structure of the fusion-active gp41, had a T m of 64°C. Different from T-20 (brand name Fuseon), which is the first and only HIV-1 fusion inhibitor approved for clinical use, CP621-652 could efficiently block 6-HB formation in a dose-dependent manner. Significantly, CP621-652 had potent inhibitory activity against HIV-1-mediated cell-cell fusion and infection, especially against T-20- and C34-resistant virus. Therefore, our works provide important information for understanding the core structure of the fusion-active gp41 and for designing novel anti-HIV peptides.

scholarly journals Alpha Interferon Potently Enhances the Anti-Human Immunodeficiency Virus Type 1 Activity of APOBEC3G in Resting Primary CD4 T Cells

2006 ◽  
Vol 80 (15) ◽  
pp. 7645-7657 ◽  
Author(s):  
Keyang Chen ◽  
Jialing Huang ◽  
Chune Zhang ◽  
Sophia Huang ◽  
Giuseppe Nunnari ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Innate Immunity ◽  
T Cells ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cd4 T Cells ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT The interferon (IFN) system, including various IFNs and IFN-inducible gene products, is well known for its potent innate immunity against wide-range viruses. Recently, a family of cytidine deaminases, functioning as another innate immunity against retroviral infection, has been identified. However, its regulation remains largely unknown. In this report, we demonstrate that through a regular IFN-α/β signal transduction pathway, IFN-α can significantly enhance the expression of apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) in human primary resting but not activated CD4 T cells and the amounts of APOBEC3G associated with a low molecular mass. Interestingly, short-time treatments of newly infected resting CD4 T cells with IFN-α will significantly inactivate human immunodeficiency virus type 1 (HIV-1) at its early stage. This inhibition can be counteracted by APOBEC3G-specific short interfering RNA, indicating that IFN-α-induced APOBEC3G plays a key role in mediating this anti-HIV-1 process. Our data suggest that APOBEC3G is also a member of the IFN system, at least in resting CD4 T cells. Given that the IFN-α/APOBEC3G pathway has potent anti-HIV-1 capability in resting CD4 T cells, augmentation of this innate immunity barrier could prevent residual HIV-1 replication in its native reservoir in the post-highly active antiretroviral therapy era.

scholarly journals Characterization of Human Class-Switched Polymeric (Immunoglobulin M [IgM] and IgA) Anti-Human Immunodeficiency Virus Type 1 Antibodies 2F5 and 2G12

2003 ◽  
Vol 77 (7) ◽  
pp. 4095-4103 ◽  
Author(s):  
Susanne Wolbank ◽  
Renate Kunert ◽  
Gabriela Stiegler ◽  
Hermann Katinger
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunoglobulin M ◽  
Mucosal Transmission ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT We have previously generated human monoclonal anti-human immunodeficiency virus type 1 (anti-HIV-1) antibodies 2F5IgG and 2G12IgG with an exceptional cross-clade neutralizing potential. 2F5IgG and 2G12IgG passively administrated to macaques were able to confer complete protection from both intravenous and mucosal challenge with pathogenic HIV-simian immunodeficiency virus chimeric strains and have shown beneficial effects in a phase-1 clinical trial. We now class-switched 2F5 and 2G12 to the immunoglobulin M (IgM) or IgA isotype, to enforce features like avidity, complement activation, or the potential to neutralize mucosal transmission. For this purpose we expressed functional polymeric 2F5 and 2G12 antibodies in CHO cells and evaluated their anti-HIV-1 activity in vitro. The class switch had a strong impact on the protective potential of 2F5 and 2G12. 2G12IgM inhibited HIV-1 infection of peripheral blood mononuclear cell cultures up to 28-fold-more efficiently than the corresponding IgG and neutralized all of the primary isolates tested. The 2F5 and 2G12 antibodies of all isotypes were able to interact with active human serum to inhibit viral infection. Furthermore, we demonstrated that polymeric 2F5 and 2G12 antibodies but not the corresponding IgGs could interfere with HIV-1 entry across a mucosal epithelial layer in vitro. Although polymeric 2F5 antibodies had only limited potential in the standard neutralization assay, the results from the mucosal assay suggest that 2F5 and 2G12 antibodies may have a high potential to prevent natural HIV-1 transmission in vivo.

scholarly journals Fruit-Specific Expression of the Human Immunodeficiency Virus Type 1 Tat Gene in Tomato Plants and Its Immunogenic Potential in Mice

2007 ◽  
Vol 14 (6) ◽  
pp. 685-692 ◽  
Author(s):  
Yuri Jorge Peña Ramírez ◽  
Ennio Tasciotti ◽  
Abel Gutierrez-Ortega ◽  
Alberto J. Donayre Torres ◽  
María Teresa Olivera Flores ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Tomato Fruit ◽  
Enzyme Linked Immunosorbent Assay ◽  
Potential Candidate ◽  
Tat Protein ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) Tat protein is considered a potential candidate vaccine antigen. In an effort to design a strategy for noninvasive vaccination against HIV-1, we developed transgenic tomatoes expressing the Tat protein. Two independent plants testing positive in transgene detection analysis were selected and grown to maturity. Monoclonal antibodies against Tat recognized a protein of the expected size. Interestingly, expression of Tat seemed to be toxic to the plant, as in all cases the fruit exhibited underdeveloped reproductive structures and no seeds. Nine groups of 10 pathogen-free BALB/c male mice were primed either orally, intraperitoneally, or intramuscularly with 10 mg of tomato fruit extract derived from transgenic or wild-type plants and with 10 μg of Tat86 recombinant protein. Mice were immunized at days 0, 14, and 28, and given boosters after 15 weeks; sera were drawn 7 days after each booster, and the antibody titer was determined by enzyme-linked immunosorbent assay. All three immunization approaches induced the development of a strong anti-Tat immunological response, which increased over time. Isotype subclass determination showed the presence of mucosal (immunoglobulin A) immunity soon after the beginning of the oral immunization protocol, and the data were confirmed by the presence of anti-Tat antibodies in fecal pellets and in vaginal washes. We also demonstrated that sera from immunized mice inhibited with high efficiency recombinant Tat-dependent transactivation of the HIV-1 long terminal repeat promoter. This neutralization activity might be relevant for the suppression of extracellular Tat activities, which play an important role in HIV disease development.

scholarly journals Genetic Analysis of the Localization of APOBEC3F to Human Immunodeficiency Virus Type 1 Virion Cores

2014 ◽  
Vol 89 (4) ◽  
pp. 2415-2424 ◽  
Author(s):  
John P. Donahue ◽  
Rebecca T. Levinson ◽  
Jonathan H. Sheehan ◽  
Lorraine Sutton ◽  
Harry E. Taylor ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cytidine Deaminase ◽  
Cytidine Deaminases ◽  
Terminal Domain ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTMembers of the APOBEC3 family of cytidine deaminases vary in their proportions of a virion-incorporated enzyme that is localized to mature retrovirus cores. We reported previously that APOBEC3F (A3F) was highly localized into mature human immunodeficiency virus type 1 (HIV-1) cores and identified that L306 in the C-terminal cytidine deaminase (CD) domain contributed to its core localization (C. Song, L. Sutton, M. Johnson, R. D'Aquila, J. Donahue, J Biol Chem287:16965–16974, 2012,http://dx.doi.org/10.1074/jbc.M111.310839). We have now determined an additional genetic determinant(s) for A3F localization to HIV-1 cores. We found that one pair of leucines in each of A3F's C-terminal and N-terminal CD domains jointly determined the degree of localization of A3F into HIV-1 virion cores. These are A3F L306/L368 (C-terminal domain) and A3F L122/L184 (N-terminal domain). Alterations to one of these specific leucine residues in either of the two A3F CD domains (A3F L368A, L122A, and L184A) decreased core localization and diminished HIV restriction without changing virion packaging. Furthermore, double mutants in these leucine residues in each of A3F's two CD domains (A3F L368A plus L184A or A3F L368A plus L122A) still were packaged into virions but completely lost core localization and anti-HIV activity. HIV virion core localization of A3F is genetically separable from its virion packaging, and anti-HIV activity requires some core localization.IMPORTANCESpecific leucine-leucine interactions are identified as necessary for A3F's core localization and anti-HIV activity but not for its packaging into virions. Understanding these signals may lead to novel strategies to enhance core localization that may augment effects of A3F against HIV and perhaps of other A3s against retroviruses, parvoviruses, and hepatitis B virus.

scholarly journals Highly Potent Inhibition of Human Immunodeficiency Virus Type 1 Replication by TAK-220, an Orally Bioavailable Small-Molecule CCR5 Antagonist

2005 ◽  
Vol 49 (8) ◽  
pp. 3474-3482 ◽  
Author(s):  
Katsunori Takashima ◽  
Hiroshi Miyake ◽  
Naoyuki Kanzaki ◽  
Yoshihiko Tagawa ◽  
Xin Wang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Host Cells ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT TAK-220 is a member of a novel class of chemokine receptor antagonists and is highly specific to CCR5, as determined by receptor binding and calcium mobilization assays. The compound selectively inhibited coreceptor-mediated entry of human immunodeficiency virus type 1 (HIV-1) into host cells and HIV-1 infection mediated by CCR5. TAK-220 inhibited the replication of six CCR5-using (R5) HIV-1 clinical isolates in peripheral blood mononuclear cells (PBMCs) with a mean 90% effective concentration of 13 nM. The anti-HIV-1 activity of TAK-220 was not affected by addition of high concentrations of human serum. It equally inhibited R5 HIV-1 replication in PBMCs obtained from eight different donors, irrespective of the levels of viral production. Furthermore, the anti-HIV-1 activity of TAK-220 was found to be subtype independent. TAK-220 did not induce CCR5 internalization but blocked the binding of two monoclonal antibodies that recognize the second extracellular loop of CCR5 in CCR5-expressing cells. These results suggest that TAK-220 selectively inhibits R5 HIV-1 replication by interfering with coreceptor-mediated entry of the virus into host cells. At a dose of 5 mg/kg of body weight, TAK-220 showed oral bioavailabilities of 9.5 and 28.9% in rats and monkeys, respectively. Thus, TAK-220 is a promising candidate for the treatment of HIV-1 infection.

Sign in / Sign up

Export Citation Format

Share Document